Method For The Production Of Albumen Conjugates With Non-Steroidal Antirheumatic Drugs (Nsar)

Abstract

The present invention concerns NSAR (non-steroidal antirheumatic agents)-protein conjugates and in particular NSAR-albumin conjugates, processes for their production and their use as pharmaceutical preparations especially for treating inflammations.

1 . Use of an NSAR-albumin conjugate comprising a non-steroidal antirheumatic agent (NSAR) and albumin for producing a pharmaceutical agent to treat rheumatoid arthritis,
 characterized in that   in the conjugate the NSAR is directly covalently bound to the albumin and the molar ratio of NSAR:albumin is in the range of about 2:1 to 0.1:1, wherein the conjugate is obtainable by reacting an NSAR and albumin in the presence of N-(3-dimethylamino-propyl)-N′-ethylcarbonyldiimide as the sole activation reagent in an organic solvent.   
   
   
       2 . The use according to  claim 1 ,
 characterized in that   the albumin is human albumin.   
   
   
       3 . The use according to  claim 1 ,
 characterized in that   the albumin is present in native form.   
   
   
       4 . The use according to  claim 1 ,
 characterized in that   the NSAR is selected from the group consisting of acetylsalicylic acid, diclofenac, indomethacin, naproxen, flufenamic acid, mefenamic acid, tolmetin, ibuprofen, fenoprofen, ketoprofen, acemetacin and niflumic acid.   
   
   
       5 . The use according to  claim 1 ,
 characterized in that   the molar ratio of NSAR:albumin is in the range of about 1.1:1 to 0.5:1.   
   
   
       6 . A process for the production of a conjugate comprising the reaction of an NSAR with albumin by direct covalent coupling,
 characterized in that   an NSAR and albumin are reacted in the presence of N-(3-dimethylamino-propyl)-N′-ethylcarbonyldiimide as the sole activation reagent in an organic solvent,   wherein the molar ratio of NSAR:human albumin is in the range of about 2:1 to 0.1:1.   
   
   
       7 . The process according to  claim 6 ,
 characterized in that   the NSAR is reacted in an anhydrous organic solvent with N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide as the sole activation reagent, is activated by heating and subsequently the NSAR is reacted with human albumin.   
   
   
       8 . An NSAR-albumin conjugate comprising an NSAR and albumin that is obtainable by the process according to  claim 6 . 
   
   
       9 . The NSAR-albumin conjugate according to  claim 8 ,
 characterized in that   the albumin is human albumin.   
   
   
       10 . The NSAR-albumin conjugate according to  claim 8 ,
 characterized in that   the albumin is present in a native form.   
   
   
       11 . The NSAR-albumin conjugate according to  claim 8 ,
 characterized in that   the NSAR is selected from the group consisting of acetylsalicylic acid, diclofenac, indomethacin, naproxen, flufenamic acid, mefenamic acid, tolmetin, ibuprofen, fenoprofen, ketoprofen, acemetacin and niflumic acid.   
   
   
       12 . The NSAR-albumin conjugate according to  claim 8 ,
 characterized in that   the molar ratio of NSAR:albumin is in the range of about 1.1:1 to 0.5:1.   
   
   
       13 . A pharmaceutical agent containing an NSAR-albumin conjugate according to  claim 8  as the active substance.